Jeffrey J. Molldrem, M.D.
Stem Cell Transplantation and Cellular Therapy
University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 0900, SCR3.3011
Houston, TX 77030
United States of America
(713) 404-2118 pager
Our laboratory studies how T cells mediate blood cytopenia by targeting hematopoietic progenitor cells in bone marrow failure disorders and how allogeneic T cells mediate the graft-versus-leukemia (GVL) effect, which maintains long term remission after allogeneic stem cell transplantation (SCT). The long-term goal is to improve our understanding of GVL mechanisms so that we can devise highly targeted immune therapies for hematological malignancies that do not increase graft-versus-host immunity, an often-lethal complication of SCT that lacks effective treatment. Our work is focused on five areas of basic and translational investigation:
- Our lab identified the PR1 9-mer peptide, derived from proteinase 3 (P3) and neutrophil elastase (NE), as an important HLA-A2-restricted leukemia-associated antigen (LAA) and we are conducting multiple PR1 vaccine studies, including a pivotal phase 3 multinational trial, and studies that combine adoptive cell therapy plus PR1 vaccination for acute and chronic myeloid leukemia (AML and CML, respectively). Thus far, the vaccine induces immune responses with minimal side effects and may induce long-term molecular remission in treatment-refractory leukemia patients.
- We have produced a T cell receptor (TCR)-like monoclonal antibody (mAb) that binds with high affinity to a conformational epitope of PR1/HLA-A2 called 8F4. The 8F4 mAb preferentially eliminates AML but not normal hematopoietic cells, potentially through a complement-dependent mechanism. In a xenogeneic mouse model, 8F4 eliminated human leukemia stem cells and significantly increased survival of treated animals. Thus, 8F4 is the first mAb that can eliminate human cancer stem cells in vivo. We are developing a fully humanized 8F4 mAb for clinical testing.
- We are studying whether P3 and NE might function as tumor-associated antigens in non-hematopoietic tumors that lack endogenous expression. P3 and NE are abundant throughout the body, particularly at inflammatory sites and in the cancer microenvironment, and they regulate inflammation after they are secreted by activated neutrophils. After cell uptake of soluble P3 and NE, we found that PR1 is cross-presented on HLA-A2 molecules on breast cancer cells. Furthermore, PR1-specific cytotoxic T lymphocytes (PR1-CTL) and 8F4 mAb mediate lysis of breast cancer co-incubated with soluble P3 or NE. These observations link two immune regulatory proteins, which are normally only expressed in neutrophils and are secreted after cell activation, with a specific adaptive immune response against the P3- and NE-derived PR1 peptide following cross presentation on the malignant cell. This new mechanism linking inflammation and innate immunity to adaptive anticancer immunity is under investigation in our laboratory.
- We identified a novel enzyme-independent inhibitory function of soluble and neutrophil membrane-bound P3 on T cell proliferation, a new mechanism linking inflammation, autoimmunity, and cancer immunity. High P3 concentrations completely and reversibly inhibit CD4 and CD8 T cell proliferation by blocking the cell cycle G1-S transition, and inhibition is blocked by autoantibodies to P3 (cANCA) from patients with systemic vasculitis. The role of P3 in regulating autoimmunity and in preventing anticancer immunity, including CD8 T cell immunity against the P3-derived PR1 peptide, is being investigated in mouse models and in humans.
- Our found PR1-CTLs are significantly increased in fetal cord blood (CB) compared to adult peripheral blood and we are studying mechanisms that lead to incomplete central tolerance to the PR1 self-peptide antigen. We discovered an absence of PR1 on thymic epithelial cells and only modest expression on cortical-medullary dendritic cells in human thymus. Relative low P3 and PR1 peptide expression in thymic tissue could prevent the deletion of developing PR1-specific T cells, which is a common mechanism resulting in negative selection. Nevertheless, the high PR1-CTL frequency of PR1-CTL in CB suggests they could be useful in the CB transplant setting as a source of naïve PR1-CTL that could be transferred after minimal ex vivo cell manipulation to patients as post-transplant adoptive T cell therapy of PR1-expressing leukemia. This hypothesis is being tested in a preclinical xenogeneic mouse model of GVL, and in the clinic with adoptively transferred CB-derived PR1-CTL.